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PubMed1984

Quantification of imipramine and its major metabolites in whole blood, brain, and other tissues of the rat by liquid chromatography.

An assay procedure is presented using high-performance liquid chromatography and fluorescence detection for simultaneous determination of imipramine, desipramine, and their 2-hydroxylated metabolites in whole blood and various tissues of the rat. By modifying methods previously described for plasma, we have developed an assay method for sensitive, reproducible quantitation of these compounds in rat plasma, whole blood, brain, liver, and fetus. Increasing the volume of the extraction solvent (20% butanol in hexane) increased recovery of imipramine and desipramine to greater than 90% for all tissues examined. No interfering peaks were observed for any of the tissues studied. Addition of n-butylamine as a modifier to the mobile phase decreased the retention of all four compounds and decreased peak tailing of the demethylated compounds. The total elution time was less than 15 min. Using these methods the coefficient of variation for all four compounds was generally less than 5% for each of the five tissues examined. The calibration curves were linear for standard concentrations of 25-2,000 ng/ml spiked tissue homogenate. This method has sufficient sensitivity and specificity for use in pharmacokinetic studies of imipramine.

Animals↗
PubMed1981

Supersensitivity to L-5-hydroxytryptophan after 5,7-dihydroxytryptamine injections in desmethylimipramine- and nomifensine-pretreated rats: behavioral evidence for postsynaptic supersensitivity.

The behavioral syndrome induced by L-5-hydroxytryptophan (L-5-HTP) in rats was used to study the supersensitivity to L-5-HTP and 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) which develops after unilateral intracerebroventricular (ICV) injections of 200 microgram 5,7-dihydroxytryptamine (5,7-DHT). Pretreatment of the animals with a combination of desipramine and nomifensine was found to protect dopamine neurones better than desipramine alone. Maximal behavioral supersensitivity to L-5-HTP and 5-MeODMT was found as early as 24 h after injection of the neurotoxin, even in the presence of the specific 5-HT uptake inhibitor CGP 6085 A, or the MAO-A inhibitor clorgyline. The results indicate that a quickly occurring postsynaptic event contributes to the development of behavioral supersensitivity after ICV injections of 5,7-DHT.

5,7-Dihydroxytryptamine↗
PubMed1989

Effects of centrally acting beta adrenergic agonists on discrete trial conditioned avoidance behavior in rats.

The acute effects of centrally acting beta adrenergic agonists on discrete trial conditioned avoidance responding in rats were examined. Clenbuterol (0.01-3.0 mg/kg), salbutamol (0.01-30 mg/kg), and prenalterol (30-300 mg/kg) suppressed avoidance responding in a dose-dependent manner at doses that did not produce escape failures. For comparative purposes, the effects of the tricyclic antidepressant desipramine (1.0-30 mg/kg) and the antipsychotic haloperidol (0.03-0.3 mg/kg) were similarly assessed. Both compounds suppressed avoidance responding in a dose-dependent manner. Only haloperidol (0.3 mg/kg) produced escape failures. Administered alone, the beta adrenergic antagonist propranolol (1.0 and 10 mg/kg) did not affect avoidance behavior. When administered prior to clenbuterol (0.1 mg/kg), salbutamol (1.0 mg/kg), or prenalterol (100 mg/kg), propranolol antagonized the beta adrenergic agonist-induced suppression of avoidance responding. The suppressive effect of desipramine (3.0 mg/kg) on avoidance performance only tended to be attenuated by propranolol. Propranolol had no effect on the ability of haloperidol (0.1 mg/kg) to reduce avoidance responding. These results suggest that the effects of the beta adrenergic agonists clenbuterol, salbutamol, and prenalterol on discrete trial avoidance behavior are mediated, in part, through agonist interactions with beta adrenergic receptors.

Adrenergic beta-Agonists↗
PubMed1975

On the mechanism of the accumulation of 3H-bretylium in peripheral sympathetic nerves.

The uptake of bretylium-(N-3H-methyl) iodide in the rat heart atrium in vitro was examined. The uptake was linear for at least 1 hr and was strongly inhibited by (+)-amphetamine, (-)-noradrenaline, desipramine, cocaine, DSP 4 [N-(2-bromobenzyl)-N-(2-chloroethyl)ethylamine hydrochloride], guanethidine and ouabain. The amphetamine sensitive part of the uptake was almost completely abolished by pre-treatment of the rats with 6-hydroxydopamine and was dependent on the presence of sodium ions. Reserpine had no effect. (+)-Amphetamine but not desipramine caused an increase of the efflux of bretylium from the tissue. The apparent Km value of the active bretylium uptake was 3 x 10(-6) M, which was 10 times higher than that of the uptake of (-)-noradrenaline in the rat heart atrium (Km = 3 x 10(-7) M). The inhibition constants (Ki) for bretylium in inhibiting the noradrenaline uptake and for (-)-noradrenaline in inhibiting the bretylium uptake were 7 x 10(-6) M and 4 x 10(-7) M, respectively. The results obtained support the hypothesis that bretylium is taken up by the same mechanism as that carrying noradrenaline into the nerve terminals but is not bound in the noradrenaline storage vesicles.

Animals↗
PubMed1981

Cerebral pharmacokinetics of imipramine in rats after single and multiple dosages.

Pharmacokinetics of imipramine (IMI) and its active metabolite, desipramine (DMI) was studied in rats after administration of a single dose of 10 mg/kg IMI, or after chronic administration of this dose once or twice a day for 14 days. The elimination curves of IMI and DMI from the blood and brain show that both the whole body and the brain behave as multi-compartment systems. Maximum concentrations of IMI and DMI in blood and brain appear at the same time, indicating rapid metabolism of IMI: the concentrations were significantly higher in the brain than in the blood. After the chronic treatment the maximum blood and cerebral levels of IMI and DMI were not much higher than after a single dose, but the elimination was slowed down. Brain concentration of IMI and DMI and brain IMI/DMI concentration ratio do not parallel those in the blood. After a prolonged treatment, once or twice a day, desipramine in the brain is present for the whole period between injections at concentrations sufficient to inhibit the noradrenaline uptake. If the drug is given twice a day, in addition to DMI also IMI is present for the whole time at concentration which may inhibit also serotonin uptake.

Animals↗
PubMed1984

Estimation of intrasynaptic norepinephrine concentrations at vascular neuroeffector junctions in vivo.

We estimated vascular neuroeffector junctional norepinephrine concentrations and their relation to pressor responses by measuring plasma norepinephrine levels and blood pressure during sympathetic stimulation or norepinephrine infusion in pithed, vagotomized, alpha 2-adrenoceptor blocked, adrenal-demedullated rats with and without uptake1 blockade by desipramine. For an increment in mean arterial pressure of 50 mm Hg, the estimated mean junctional norepinephrine concentration ( ES50m ) was about 7 nmol/l. Norepinephrine concentration gradients between the site of norepinephrine release and plasma appeared to be equal and reciprocal for sympathetic stimulation and for norepinephrine infusion. These gradients were reduced equally (by about two-thirds) after desipramine treatment, indicating that removal of both released and infused norepinephrine is mainly by neuronal uptake.

Animals↗
PubMed1986

Choline+: a substrate of the neuronal noradrenaline carrier in the rat vas deferens.

The effects of choline+ (10-40 mmol/l) on 3H-noradrenaline uptake by, and 3H-noradrenaline efflux from, noradrenergic neurones were studied in vasa deferentia of reserpine-pretreated rats at an external Na+ concentration of 100 mmol/l. Monoamine oxidase and catechol-O-methyltransferase were inhibited. Choline+ (20 and 40 mmol/l) competitively inhibited the neuronal uptake of 3H-noradrenaline. From the choline+-induced changes in the apparent Km for 3H-noradrenaline transport, a Ki of 35 mmol/l was obtained. Choline+ (10, 20 and 40 mmol/l) accelerated the neuronal efflux of 3H-noradrenaline in a concentration-dependent manner. This acceleration of efflux was greatly reduced in the presence of 1 mumol/l desipramine, indicating that choline+ is capable of eliciting "accelerative exchange diffusion". Choline+ (40 mmol/l) and (-)noradrenaline (4.5 mumol/l) (i.e., concentrations about equivalent to the Ki and Km for choline+ and (-)noradrenaline, respectively) produced virtually identical increases in the neuronal efflux of 3H-noradrenaline. Choline+ (3-300 mmol/l) inhibited the specific binding of 3H-desipramine to plasma membranes derived from cultured rat phaeochromocytoma (PC-12) cells. The Ki for this interaction was 48 mmol/l. This results suggest that choline+ acts as alternative substrate of the neuronal noradrenaline transport system and should, therefore, not be used in transport studies with noradrenaline as substitute for Na+ in Na+-deficient media.

Animals↗
PubMed1982

Involvement of catecholamines in Haemophilus influenzae induced decrease of beta-adrenoceptor function.

The deeper airways of patients with asthmatic bronchitis are often infected with Haemophilus influenzae. Vaccination of guinea pigs with H. influenzae resulted in a significant impairment of the isoproterenol induced relaxation of isolated tracheal spirals by approximately 50% 4 days following vaccination. In the present study we further investigated the effects of some drugs affecting catecholamine release on the H. influenzae induced functional desensitization of tracheal spirals. Benserazide, an inhibitor of dopa-decarboxylase, completely prevented the reduction in isoproterenol-induced relaxation after H. influenzae vaccination, while no effect on relaxation of tracheal spirals from control animals was detected. On the other hand, inhibiting the re-uptake of catecholamines with desipramine did not influence the relaxation in the H. influenzae vaccinated tracheal spirals. Treatment of control animals with desipramine however resulted in a decreased relaxation of the isolated spirals by 40%. One day following vaccination with H. influenzae the level of norepinephrine in lung tissue was significantly elevated by 71%, and in plasma by 77%, while after 4 days no significant effects were observed. The spontaneous release of norepinephrine, epinephrine and dopamine of tracheal incubates was increased at days 1 and 4 following vaccination. The release of catecholamines from minced lung incubates of H. influenzae pretreated guinea pigs did not differ from that of controls. On the basis of these results it may be suggested that catecholamine metabolism is changed in lungs from H. influenzae vaccinated animals. Catecholamines, accordingly may play a role in the desensitization of beta-adrenoceptors by H. influenzae.

Animals↗
PubMed1986

Effects of clonidine on the stimulation-evoked release of 3H-noradrenaline from superfused rat brain slices as a function of the biophase concentration. Temperature dependent widening of extracellular space.

The influence of clonidine on the stimulation-evoked overflow of tritium was studied in brain slices preincubated with 3H-noradrenaline. The slices were prepared from parietal cortex (Cx), nucleus anterior hypothalami (nah) and nucleus tractus solitarii (nts). After preincubation, the tissues were superfused at 23 degrees C or 37 degrees C with a medium containing the noradrenaline uptake inhibitor desipramine. Electrical field stimulation was applied using stimulation frequencies of 0.3-10 Hz. At 23 degrees C/0.3 Hz, clonidine concentration-dependently inhibited the evoked overflow of tritium in all three brain regions. In contrast, at 23 degrees C/3 Hz the inhibitory effect of the drug in the Cx was abolished and a facilitation was observed in the nah and nts. When tested at increasing frequencies of stimulation in the nts at 23 degrees C, clonidine exerted a dual action, characterized by a reduction of electrically evoked responses at frequencies below 1 Hz and a facilitation at frequencies above 1 Hz. At 37 degrees C, clonidine concentration-dependently decreased the evoked overflow in all brain regions studied, this effect being more pronounced at 0.3 Hz than at 3 Hz. The apparent lack of an effect of clonidine on the stimulation-evoked overflow of tritium in the Cx at 23 degrees C/3 Hz was turned to a facilitation when noradrenaline (0.01 mumol/l) was included in the superfusion medium. Conversely, an inhibitory effect of clonidine was seen when the uptake blocker desipramine (as well as noradrenaline) was omitted from the superfusion medium.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Effects of chronic antidepressant treatment on dopamine-related [3H]SCH 23390 and [3H]spiperone binding in the rat striatum.

1. The effects of chronic administration of antidepressants on dopamine-related [3H]SCH 23390 and [3H]spiperone binding to rat striatal membranes were assessed. 2. The monoamine oxidase inhibitors phenelzine (5 or 10 mg kg-1/day) and tranylcypromine (1 mg kg-1/day) and the tricyclic desipramine (10 mg kg-1/day) were administered for 28 days by constant subcutaneous infusion using Alzet (2ML4) osmotic minipumps. 3. These treatments did not alter Kd estimates for either [3H]SCH 23390 or [3H]spiperone binding sites. The monoamine oxidase inhibitors induced a decrease in the Bmax values for both [3H]SCH 23990 and [3H]spiperone binding sites. Desipramine induced a decrease in the Bmax value for [3H]SCH 23390 binding but had no effect on the Bmax value for [3H]spiperone binding.

Animals↗
PubMed1988

Assessment of rat brain alpha 1-adrenoceptor binding and activation of inositol phospholipid turnover following chronic imipramine treatment.

Chronic (21 days) treatment of rats with imipramine (10 mg/kg) did not change the density or affinity of alpha 1-adrenoceptors as measured by the specific binding of [3H]prazosin in rat cortical membranes, but produced the expected significant decrease in the density of beta-adrenoceptors labeled by [125I]iodocyanopindolol. The functional status of brain alpha 1-adrenoceptors was also assessed by measuring the noradrenaline (NA)-induced accumulation of [3H]inositol 1-phosphate (IP1) in brain slices from these animals. No apparent change was observed in the concentration-response relationship between NA and [3H]IP1 accumulation in rat cerebral cortex after chronic treatment with imipramine. At concentrations higher than 1 microM in vitro, imipramine and its metabolite, desipramine, produced a concentration-dependent decrease in the [3H]IP1 accumulation elicited by NA. This inhibitory effect is likely mediated by direct blockade of alpha 1-adrenoceptors by these drugs. As the endogenous drug concentration would not reach 1 microM in our preparation, the lack of changes in alpha 1-adrenoceptor response following chronic imipramine treatment are not likely attributable to residual imipramine or desipramine retained in the tissues. In conclusion, the above findings do not support previous suggestions that brain alpha 1-adrenoceptors are upregulated following chronic imipramine administration.

Animals↗
PubMed1993

The potentiation of cortical neuron responses to noradrenaline by 2-phenylethylamine is independent of endogenous noradrenaline.

2-Phenylethylamine (PE) is an endogenous brain amine which produces sympathomimetic responses and potentiates cortical neuron responses to noradrenaline (NA). In order to examine further the mechanism of action of PE, extracellular recordings were made of the activity of single neurones in the cerebral cortex in urethane-anesthetized rats. Sympathomimetic responses to PE were blocked by pretreatment with reserpine, reserpine plus alpha-methyl-p-tyrosine and desipramine. It is concluded that the sympathomimetic responses to PE are indirect. 2-Phenylethylamine potentiated cortical neuron responses to electrical stimulation of the locus coeruleus in a dose-dependent manner. This was seen when PE was given systemically (with as little as 1 microgram/kg) and iontophoretically. The effects of PE were not reproduced by its metabolite phenylacetic acid or its putative metabolite phenylethanolamine. Iontophoretic applications of PE (0-6 nA, 2-5 minutes) potentiated cortical neuron responses to iontophoretically applied NA, without affecting the spontaneous firing rate, or the responses to iontophoretically applied GABA or acetylcholine. This effect of PE was not blocked by pretreatment with alpha-methyl-p-tyrosine or desipramine, and was potentiated by pretreatment with reserpine and reserpine plus alpha-methyl-p-tyrosine. It is probable that the ability of PE to modulate neuronal responses to NA does not involve the presynaptic NA terminal or endogenous NA and it is likely that PE acts directly to increase the efficacy of NA. These findings are consistent with the hypothesis that the physiological role of PE is to modulate catecholaminergic transmission within the central nervous system.

Animals↗
PubMed1985

Effects of combined administration of L-tryptophan and tricyclic antidepressants on alpha 2- and beta-adrenoceptors and monoamine levels in rat brain.

In order to test whether co-administration of a serotonin precursor with antidepressant drugs could potentiate the effects of the antidepressants on monoamines or adrenoceptors in rat brain, L-tryptophan (20 mg/kg) was administered to rats daily for 7 or 15 days, either alone or in combination with desipramine (10 mg/kg) or amitriptyline (10 mg/kg). After treatment with L-tryptophan for 7 days, increases were observed in rat hypothalamic and frontal cortex 5-hydroxy-3-indoleacetic acid levels as well as in hypothalamic dopamine and nucleus accumbens 3,4-dihydroxyphenylacetic acid levels. After 15 days, hippocampal beta-adrenoceptor density was found to be decreased. There was no evidence of potentiation of desipramine or amitriptyline action when L-tryptophan was administered in combination with the antidepressants. On the contrary, the antidepressants appeared to interact with L-tryptophan to reduce its effects.

Amitriptyline↗
PubMed1982

Sensitivity in vivo of central alpha 2- and opiate receptors after chronic treatment with various antidepressants.

Recent studies suggest that the antidepressant activity could be explained by gradually developing modifications in the sensitivity of some central monoaminergic receptors. As concerns alpha 2-receptors, some largely indirect informations suggest that a subsensitivity develops following chronic treatment with desipramine or imipramine. However it is not clear whether this effect is shared by other antidepressants. In view of the important role of these receptors in the regulation of noradrenergic neuro-transmission, single cell recording and microiontophoretic techniques were used in this work to systematically assess locus coeruleus (L.C.) alpha 2-receptor sensitivity following acute and chronic administration of various antidepressants. The responsiveness of L.C. alpha 2-receptors to iontophoretically applied clonidine was studied simultaneously with the responsiveness of L.C. opiate receptors to iontophoretically applied morphine in order to test the specificity in the putative modifications induced by the antidepressants. The compounds studied were desipramine (DMI), imipramine (IMI), clomipramine (CIMI), zimelidine (ZIM), mianserin (MIAN), iprindole (IPR) and chlorpromazine (CPZ). Long-term treatment with DMI, IMI and ZIM but not with the other clinically effective antidepressant drugs induced a decrease in the responsiveness of L.C. neurons to iontophoretically applied clonidine. None of the drugs tested altered the responsiveness of these neurons to iontophoretically applied morphine. Consequently the therapeutic effectiveness of antidepressant drugs can not be generally related to modulation of the sensitivity of central alpha 2- or opiate receptors.

Animals↗
PubMed1992

Changes in the amount and distribution of neuronal alkaline and acid phosphatase after chronic exposure of cultures of cingulate cortex to antidepressant drugs.

Enzyme histochemistry was used to examine alkaline and acid phosphatases in cultures of embryonic rat cingulate cortex after 14 days exposure in vitro to two tricyclic antidepressants (amitriptyline and desipramine) and two non-tricyclic antidepressants (mianserin and citalopram). An increased amount of acid phosphatase reaction product was observed in lysosomes of neurons in cultures treated chronically with the non-tricyclic antidepressants, mianserin or citalopram. More strikingly, reaction product was also present in the inner lamellae of the Golgi apparatus after this treatment, but never in controls. These observations suggest that non-tricyclic antidepressants significantly increase the rate of degradative processes in cingulate neurons. In cultures, treated chronically with desipramine or amitriptyline, pre- and postsynaptic membranes contained heavy deposits of alkaline phosphatase reaction product, whereas in control cultures not exposed to these drugs the corresponding membranes were entirely devoid of reaction product. An increase in the amount of alkaline phosphatase reaction product was also observed on the plasma membranes of neuronal cell bodies. These observations suggest that chronic exposure to antidepressants may influence transmembrane transport in cingulate neurons.

Acid Phosphatase↗
PubMed1990

Effects of chronic antidepressant treatment on alpha 1- and alpha 2-adrenoceptors in the rat anococcygeus muscle.

The effects of a single administration (48 hours) and of chronic (14 days) treatment with tricyclic (desipramine, nortryptiline) and nontricyclic (mianserin, nomifensine) antidepressant drugs on responses of the isolated anococcygeus muscle to the alpha 2-adrenoceptor agonist xylazine (inhibition of contraction to field stimulation at 1 Hz) and to the alpha 1-adrenoceptor agonist phenylephrine (contraction of the muscle) have been studied. Of the drugs used only desipramine and nortryptiline administered chronically reduced the responsiveness of the anococcygeus muscle to phenylephrine suggesting a desensitization of postsynaptic alpha 1-adrenoceptors. Long-term but not acute administration of antidepressants resulted in significant decrease in sensitivity of presynaptic alpha 2-adrenoceptors to xylazine. These results show that the adaptative changes of alpha-adrenoceptors in the rat anococcygeus muscle following long-term administration may depend on the efficiency to inhibit the neuronal uptake and the ability to antagonize alpha 1-adrenoceptors.

Animals↗
PubMed1990

Gangliosides enhance the anti-immobility response elicited by several antidepressant treatments in mice.

Ganglioside pretreatment enhanced the anti-immobility effect induced in the forced swim test after a chronic treatment with desipramine, mianserin, clomipramine, nialamide or repeated electroconvulsive shock in mice. Gangliosides, which had no effect per se, showed a clear dose-response relationship in enhancing the anti-immobility effect of desipramine. These results suggest that, regardless of their mechanisms of action, gangliosides facilitate the behavioral response of several antidepressant treatments.

Animals↗